Chirality plays a crucial part in numerous biological processes and has also acquired increasing importance for the pharmaceutical industry, as evidenced for example by the fact that of the drugs developed hitherto more than 80% have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of the enantiomeric forms is effective and is administered. For example, enzymes whose chiral components are the amino acids are able to distinguish between the individual enantiomeric forms in the body.
In particular, the enantiomers of 5,6-dihydro-4-hydroxy-2-pyrones are important structural elements in a number of pharmaceutically effective compounds, the category of the 5,6-dihydro-4-hydroxy-2-pyrone-sulphonamides being particularly important. Thus, [R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl) -6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulphonamide, known as tipranavir (PNU-140690), is a protease inhibitor which is used to treat HIV and has the following structure: 
These and other structurally similar compounds are known from the prior art (cf. for example J. Med. Chem. 1998, 41, 3467–3476).
In order therefore to prepare active substances which are as optically isomerically pure as possible, particularly with respect to the above group of compounds, it is essential to develop selective methods of synthesis. This results in a large number of processes for preparing chiral compounds, for example separation processes such as crystallisation or chromatographic methods.
Non-selective synthesis requires an additional step of separating the optical isomers, e.g. in the form of a final racemate cleaving of the two enantiomers by either chemical or enzymatic methods. It is thus plain that selective syntheses which lead to only one optical isomer (either enantiomer or diastereomer) are advantageous. Thus, so-called asymmetric synthesis is increasingly used, i.e. preferably only one optical isomer is formed in a reaction. Enantio- or diastereoselective reactions are used not only in syntheses on a laboratory scale but also increasingly in industrial scale production.
One particularly elegant alternative method of preferentially synthesising an optical isomer is enantio- or diastereoselective catalysis with chiral catalysts. The catalysts are transition metal complexes with one or more chiral ligands. The number of possible chiral ligands is almost unimaginably great and therefore a number of combinations of metal and ligand(s) are opened up. However, this range of variation makes it difficult to arrive easily at the best combination for the product which is to be produced.
The development of new ligand systems is of enormous interest, particularly for use on an industrial scale, in terms of meeting the economic requirements such as cheap and efficient availability and high performance with regard to selectivity, yield and variability.
Asymmetric catalysis is important for a number of industrial processes and is used among other things in the production of amino acids and chiral amines and for ketone reduction. For example, the firm Degussa have developed the catalyst DeguPhos which is used for the reductive amination of alpha-keto acids, for preparing L- and D-amino acids. It is known that DuPhos ([1,5-cyclooctadiene)rhodium(I)-1,2-bis((2R,5R)-dimethyl-phospholano) benzene]tetrafluoroborate is used for the asymmetric hydrolysis of amino acids.
In addition, asymmetric hydrogenation is increasingly gaining importance as a chiral reaction. Some asymmetric hydrogenations are known on a laboratory scale for the production of small amounts but there are scarcely any large scale industrial processes in use. In order to adapt reactions of this kind to the industrial scale it is essential that the hydrogenation catalysts, particularly their ligands, have high selectivity and activity in addition to availability. Some proposals for enantioselective hydrogenation are known from the prior art: thus, the disclosure of WO 00/55150 describes a method of asymmetrically hydrogenating double bonds. Various intermediate products are prepared for the synthesis of tipranavir, while a rhodium catalyst with at least one chiral ligand containing a phosphorus atom is used. Preferably, DuPhos (1,2-bis((2R,5R)-dimethyl-phospholano)benzene) or BPE (1,2-bis((2R,5R)-dimethyl-phospholano)ethane) are used as chiral ligands.
U.S. Pat. Nos. 5,171,892, 5,532,395 or 5,559,267 describe the use of an enantioselective rhodium catalyst with DuPhos ligand, which is supposed to result in enantioselective hydrogenation in the range from 70 to 89%.
Moreover, the teaching of WO 99/12919 describes a process for preparing 4-hydroxy-2-oxo-pyran derivatives which includes, among other things, enantioselective hydrogenation with a catalyst containing DuPhos as ligand.
However, the transition metal complexes of chiral phosphane ligands mentioned above usually exhibit insufficient activity in catalytic processes of this kind, combined with only moderate stereoselectivity, with the result that it would frequently be preferable to use stoichiometric quantities of chiral hydride reagents. There is therefore still a need to develop a stereoselective hydrogenation catalyst which overcomes these disadvantages.
The problem of the invention is, therefore, as a continuation of the prior art, to provide a process which allows enantio- or diastereoselective hydrogenation in high yields, with a high enantio- or diastereoselectivity, with the lowest possible technical expenditure and a high space/time yield. This process should also be suitable for scaling up to an industrial scale, i.e. it should be cheap and therefore economical to carry out. Moreover, in the compounds which are provided according to the invention which are of central importance in the synthesis of the pharmaceutically active compounds mentioned above, the chiral information contained in the starting compounds should not be lost during hydrogenation and other groups present in the molecule should not be affected by the hydrogenation. Thus, a process according to the invention is to be provided by which only one specific double bond is selectively hydrogenated to form, if possible, only one optical isomer.